Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease that affects about 1% of the global population, with a female-male ratio of 3:1. To date, genetic predisposition, the involvement of a deficient immune system and lifestyle are known to be the major responsible for the onset of the disease. RA preferably affects the joints, with consequent joint swelling and deformities followed by ankylosis. Patients suffering from rheumatoid arthritis can also develop extra-articular manifestations, which mainly affect the cardiovascular system, the nervous system, the skin, the eye, the respiratory system, the kidney and the gastrointestinal system. It has been shown that about 20% of RA patients can develop neuropathies, multiple mononeuritis, distal sensory neuropathies and sense motor neuropathies. Neurological involvement occurs as a consequence of vasculitis of the nerve vessels leading to vascular ischaemia, axonal degeneration and neuronal demyelination. In RA, the risk of developing cardiovascular disease is very high and depends, most probably, on vascular damage resulting from endothelial dysfunction. Hence, it is reasonable to assume that the integrity of the endothelium is also involved in the neurological disorders resulting from RA. This review aims to highlight the main characteristics of the extra-articular manifestations at the nervous level resulting from rheumatoid arthritis. To this end, the literature main results on these pathological manifestations have been collected with particular focus on the involvement of endothelial dysfunction. In fact, the endothelium could be considered a valuable target for minimizing the incidence of extra-articular neurological manifestations in RA.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins and decrease levels of toxic proteins. ASOs are being developed for the treatment of several diseases, including motor neuron diseases (MNDs), a group of neurodegenerative disorders characterised by the loss of motor neurons, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MND, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Introduction: The association between epilepsy and myasthenia gravis has rarely been reported, and only in small case series. Objective: To report the frequency of epilepsy and myasthenia gravis and to describe a case series of patients with myasthenia gravis and epilepsy, focusing on their clinical characteristics and searching for a possible physiopathological mechanism. Methods: A retrospective, observational, adult center study was conducted in 2022. Patients were recruited from the database of the outpatient clinic of the Myasthenia Gravis unit and Epilepsy unit. Results: Five patients were included. Frequency of epilepsy in the myasthenia gravis cohort was 5/469 (1.1%), and of myasthenia gravis in the epilepsy cohort was 5/1432 (0.35%). All patients suffered focal epilepsy, mainly fronto-central, and drug-resistant in half of them. Myasthenia gravis was generalized and with exacerbations in half of them. Three patients were thymectomized. Other autoimmune diseases were found in 2 (40%). Epilepsy onset preceded myasthenia gravis onset in all patients. Both diseases were considered autoimmune-related in 3/5 (60%). Conclusion: Epilepsy and myasthenia gravis are only infrequently associated. In adult patients, epilepsy onset precedes myasthenia onset in most cases. In some cases, epilepsy has an autoimmune aetiology and coexists with other autoimmune conditions.

Background: Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer’s disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, show membrane-binding capacity to red blood cells (RBCs) and trigger several morphological and functional alterations in RBCs that can result in impaired oxygen transport and delivery. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the role of sphingosine-1-phosphate (S1P) in signaling pathways involved in the mechanism underlying ATP release in Aβ-treated RBCs. Methods: In RBCs following different treatments, ATP, 2,3 DPG, cAMP levels, and caspase 3 activity were determined by spectrophotometric and immunoassay. Results: S1P rescued the inhibition of ATP release from RBCs triggered by Aβ through a mechanism involving caspase-3 and restoring 2,3 DPG and cAMP levels within the cell. Conclusions: These findings reveal the molecular basis of S1P protection against Aβ in RBCs and suggest new therapeutic avenues in AD.

This study proposed to use wearable EEG to study the impact of vipassana mindfulness practice on beginner's physiological and neurological responses. Mindfulness meditation has been shown to have numerous benefits, including stress reduction, improved attention and cognitive function, and enhanced emotional regulation. The roots of mindfulness meditation in Buddhism emphasize cultivating present-moment awareness and insight. However, the neural mechanisms together with physiological mechanism and their interaction underlying these benefits remain poorly understood. Method: One middle age man (50 years old) participated in this longitudinal study using wearable EEG to investigate the neurophysiological change during a one-month consecutive vipassana mindfulness practice. Both EEG and heart rate responses were recorded each time, before (5 minutes), during (20 minutes), and after (5 minutes) meditation sessions. The EEG and HR data were analyzed by Matlab and EEGlab to examine changes in brainwave activity and heart rate. Results: alpha peak frequency (APF) is significantly lower after mindfulness meditation, as shown by comparison of APF before mindfulness (pre-5) and during mindfulness practice (med-20), and comparison between APF of pre-5 and after mindfulness practice (post-5). The same is with the beta peak power. While for theta peak frequency, it is significant lower during mindfulness meditation (med-20), when comparing to either pre-5 or post-5. See figure 1a. However, peak power index is not so sensitive, and it is more obvious in theta wave band. That is, the theta power peak is significantly lower after meditation, as can be observed in comparison between pre-5 and med-20, also between pre-5 and med-20. See figure 1b. STATE Heart-mean (bpm) Heart-std(bmp) pre-5 69.88 3.88 med-20 68.36 2.81 post-5 69.55 4.13 t-value test (pre-med) 0.0694 0.0003 t-value test (pre-post) 0.7934 0.3656 t-value test (post-med) 0.3193 0.0001 Table 1. The difference of Heart rate (mean and SD) in before (pre-5), during (med-20) and after (post-5)mindfulness meditation. We find significant change in standard deviation (SD) of heart rate between meditation and non-meditation mental states, as shown in table 1. The study provides insights into the underlying neurophysiological mechanisms of mindfulness meditation using wearable EEG devices. It demonstrates that in term of EEG measurement, spectrum frequency can be more sensitive than spectrum power; also heart rate variability as measured by SD is more sensitive to mean of HR. The proposed study contributes to the literature by using wearable EEG devices to collect data in a more accessible and convenient manner.

Background: Pediatric neurological disorders include neurodegenerative disease causing cognitive impairment, vision loss to mention a few. They are one of the important causes of morbidity and mortality in children with diverse etiology. Diagnosis is difficult in spite of genetic work and in only 60% of cases final diagnosis can be achieved. Case presentation: We explore three cases of pediatric neurological diseases, viz. Arthrogryposis, congenital bilateral cataract and Autism by analyzing clinical exomes. In this work, we attempted to understand rare neurological disorders in an Indian pediatric cohort using exome studies. Conclusions: We used our benchmarked CONVEX pipeline for screening consensus variants, wherein EIF2B2 was found to be inherently pathogenic. We map the association of variants and genes, disease correlation to neuroleptic malignant syndrome which is a matching phenotype to the cases.

Neural membranes are composed of phospholipids, sphingolipids, cholesterol and proteins. In re-sponse to cell stimulation or injury, metabolism of lipids generates various lipid mediators, which perform many cellular functions. Thus, phospholipids release arachidonic acid or docosahex-aenoic acid from the sn-2 position of glycerol moiety by the action of phospholipases A2. Ara-chidonic acid is a precursor for prostaglandins, leukotrienes, thromboxane, and lipoxins. Among these mediators, prostaglandins, leukotrienes, and thromboxane produce neuroinflammation. In contrast, lipoxins produce anti-inflammatory and pro-resolving effects. Prostaglandins, leukotri-enes, and thromboxane are also involved in cell proliferation, differentiation, and blood clotting, and blood vessel permeability. In contrast, DHA-derived lipid mediators are called as specialized pro-resolving lipid metabolites (SPMs). They include resolvins, protectins, and maresins. These mediators regulate immune function by producing anti-inflammatory, pro-resolving, and cell pro-tective effects. Sphingolipid derived-metabolites are ceramide, ceramide1-phosphate, sphingosine, and sphingosine 1 phosphate. They regulate many cellular processes including enzyme activities, cell migration and adhesion, inflammation, and immunity. Cholesterol is metabolized into hy-droxycholesterols and 7-ketocholesterol, which not only disrupts membrane fluidity, but also promotes inflammation, oxidative stress, and apoptosis. These processes lead to cellular damage.

Functional neurological disorder, or FND, is widely misunderstood, particularly when considering recent research that suggests that the illness has a biological rather than a psychiatric basis. Nonetheless, the long-held view that FND is a purely psychiatric disorder without biological basis, or even a contrived (malingered) illness, remains pervasive both in modern medical care and general society. This is because FND involves an intermittent course of involuntary disability that rapidly alternates with improved neurological control. This has in turn caused shaming, low self-efficacy, and social isolation of the patients. Little research has examined the numerous biomarkers that are shared between FND and canonical neurological disorders and the encouraging outcomes that can follow conventional neurological rehabilitation, modified for this disorder. This review summarizes current research on FND biomarkers and physical rehabilitation results. General healthcare providers would benefit their care for their patients through their improved understanding the illness and recourses for support and treatment that are provided in this review.

The most recent and non-invasive approach for studying early-stage biomarkers is liquid biopsy. It implies the extraction and analysis of non-solid biological tissues (serum, plasma, saliva, urine and cerebrospinal fluid) without undergoing invasive procedures to determine disease prognosis. Liquid biopsy can be used for the screening of several components such as extracellular vesicles, microRNAs, cell-free DNA, cell-free mitochondrial and nuclear DNA, circulating tumor cells, circulating tumor DNA, transfer RNA and circular DNA or RNA derived from body fluids. Its application includes early disease diagnosis, surveillance of disease activity, and treatment response monitoring, with growing evidence for validating this methodology in cancer, liver disease, and central nervous system (CNS) disorders. This review will provide an overview of mentioned liquid biopsy components, which could serve as valuable biomarkers for the evaluation of complex neurological conditions, including Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, stroke, traumatic brain injury, CNS tumors, and neuroinfectious diseases. Furthermore, this review highlights the future directions and potential limitations associated with liquid biopsy.

Poverty has long been associated intricately with neurological disorders. Majority of the previous studies designed to describe the effects of poverty on neurological ailments have mostly linked the association of hypoxic ischemic encephalopathy and nutritional deficiency disorders with poverty. Authors herein try to delve deeper into this issue. The association of begging with neuropsychiatric disorders is robust. The burden of probable autosomal dominant neurological ailments is very common among beggars; followed by neurological disorders with social stigma like abnormal movements, facial dysmorphism and gait unsteadiness. Dearth of support from family members in autosomal dominant neurological disorders (as family members are likely to be suffering from similar neurodegenerative disorder ) and poor perception about neurological diseases, misconceptions, myths and low educational attainment at large in the society can be implicated as the often overlooked but important factors underneath this association of begging and neurological disorders.

Background and Objectives: High job strain is worsening the outcome in coronary artery disease, CAD. Severe dissatisfaction on workplace, imbalance between high demands , and low rewards, are affecting the quality of life, and diminishing the duration of life, especially in CAD patients. Our study included two samples : CAD patients (experimental group), and without CAD patients, but with traditional risk factors (control group). The main objective of the study was the role played by high sensitivity C reactive protein, hs CRP, and microalbuminuria, as mediators of job strain and CAD relationship. Secondary objectives were the following: identification of the most vulnerable patients( with significant job strain) and intervention towards this category, for cardiovascular events prevention (primary or secondary). Materials and Methods: The utilized methods were the following : clinical exam; electrocardiogram; echocardiogram; non contrast enhanced computed chest tomography; laboratory findings ( lipid profile, glycemia, hs CRP, microalbuminuria); type D scale, DS 14; depression questionnaire, PHQ-9; and satisfaction with work scale, SWWS. Results: The highest values for hs CRP and microalbuminuria were noticed in patients with the lowest Likert score, for both samples CAD, and without CAD patients. The highest job strain was noticed in females. More than half of CAD patients ,with low Likert scores, revealed myocardial infarction. Conclusions: Microalbuminuria and hs CRP were statistical significant in the study as intercessors, in job strain and CAD relationship. The most vulnerable patients for vascular events were females, in both groups : CAD and “CAD waiting desk”. In CAD sample, the vascular vulnerability was also increased by high job strain.

Diastolic dysfunction, a prevalent condition characterized by impaired relaxation and filling of the left ventricle, significantly contributes to heart failure with preserved ejection fraction (HFpEF). Galectin-3, a β-galactoside-binding lectin, has garnered attention as a potential biomarker and mediator of fibrosis and inflammation in cardiovascular diseases. This comprehensive review investigates the impact of galectin-3 on diastolic dysfunction. We explore its molecular mechanisms, including its involvement in cellular signaling pathways and interaction with components of the extracellular matrix. Evidence from both animal models and clinical studies elucidates galectin-3's role in cardiac remodeling, inflammation, and fibrosis, shedding light on the underlying pathophysiology of diastolic dysfunction. Additionally, we examine the diagnostic and therapeutic implications of galectin-3 in diastolic dysfunction, emphasizing its potential as both a biomarker and a therapeutic target. This review underscores the significance of comprehending galectin-3's role in diastolic dysfunction and its promise in enhancing diagnosis and treatment approaches for HFpEF patients.

Handedness reflects functional body and hemispheric lateralization, proving relevant to contextualize cognitive and behavioral profiles. This study aimed to determine the lateralization of the hands, feet and eyes in patients with various neurological disorders and to test the Edinburgh Handedness Inventory (EHI), a widely used handedness measure. The study design included a literature overview and a clinical study. The overview spanned the literature of the past 50 years since the EHI was developed. Three hundred seventy-four patients with immune-mediated (IM) or noIM neurological diseases and healthy subjects underwent personal and family history of handedness, stressful events and IM diseases, and EHI. The literature overview showed that handedness, which develops under the influence of genetic and acquired factors, is an indirect indicator of hemispheric lateralization; hemispheric lateralization is bidirectionally related to the immune system. In the clinical study, the EHI showed appropriate reliability and structural validity; its scores related to chronological age, onset age, and disease duration and helped distinguish patients with IM disease from other patients and healthy subjects. Therefore, handedness may change over the course of life under the influence of pathology and could predict IM neurological diseases. The EHI is an appropriate measure of handedness.

While the desire to uncover the neural correlates of consciousness has taken numerous directions, self-face recognition has been a constant in attempts to isolate aspects of self-awareness. The neuroimaging revolution of the 1990’s bought about systematic attempts to isolate the underlying neural basis self-face recognition. These studies, including some of the first fMRI (functional Magnetic Resonance Imaging) studies, revealed a right hemisphere bias for self-face recognition in a diverse set of regions including the insula, the Dorsal Frontal Lobe, the Temporal Parietal Junction and Medial Temporal Cortex. Confirmation of these data (which are correlational) was provided by TMS (Transcranial Magnetic Stimulation) and patients in which direct inhibition or ablation of right hemisphere regions leads to a disruption or absence of self-face recognition. These data are consistent with a number of theories including a right hemisphere dominance for self-awareness and/or a right hemisphere specialization for identifying significant social relationships including to oneself.

Embryologically, the left brachiocephalic vein (LBV) originates as an anastomotic channel between the right and left anterior cardinal veins 1 . This positions the LBV between the manubrium sterni anteriorly and the innominate artery posteriorly 2 . This pattern of adjacency of the aorta to the LBV is unique to mammals and results from a quirk of evolution 3 . With age, the ascending aorta unfolds, elongates and dilates 4 . Simultaneously, there is a change in the thoracic geometry that reduces the thoracic volume primarily from disc height loss and kyphosis 5 . These transitions progressively compress the LBV. Normally this compression is circumvented via collateral pathways and "Blood finds a way" 6 . However, traversing these circuitous pathways comes at a cost and can result in delayed transit times and venous congestion. While it is possible that compression of the LBV in the setting of adequate collateral channels may fail to provoke any pathologic sequelae, we propose a phenomenon in which such compression in the setting of inadequate collateral circulation may lead to a state of pathologic venous congestion. This anatomic anomaly and its associated clinical features, if identified, can offer a new avenue for treatment options for some of the hitherto unexplained neurologic disorders.

Neurological / neurovascular disorders constitute the leading cause of disability and second leading cause of deaths in the world. Some of the major neurological / neurovascular disorders or diseases include stroke, Alzheimer’s disease, spinal cord injury, neonatal hypoxic-ischemic encephalopathy, etc. Their pathophysiology is considered as highly complex and has been blamed as the main obstacle in the development of any drugs for these diseases. In this review, we have described the endothelin system, their involvement in neurovascular disorders, importance of endothelin B receptors (ETBRs) as a novel potential drug target, and its agonism by IRL-1620 (INN - sovateltide), which we are developing as a drug candidate for treating the above-mentioned neurological disorders / diseases. We have highlighted the results of our pre-clinical and clinical studies related to these diseases. The phase I, safety and tolerability study of sovateltide has shown it as a highly safe and well tolerable compound at tested dosages, while pre-clinical and clinical phase II studies have demonstrated its efficacy in treating acute ischemic stroke, where it is currently being developed as a “First in Class” drug. Its testing in Alzheimer’s disease (AD), acute spinal cord injury and neonatal hypoxic-ischemic encephalopathy (HIE) is currently being carried out and are at different stages of drug development. Successful completion of these studies will prove the involvement of ETBRs signaling in neurological / neurovascular diseases and help in development of novel neurological drugs in future.

The Coronavirus disease due to SARS-CoV-2 emerged in Wuhan city, China in December 2019 and rapidly spread more than 200 countries as a global health pandemic. There are more 3 million confirmed cases and around 207,000 fatalities. The primary manifestation is respiratory and cardiac but neurological manifestations are being reported in the literature as case reports and case series. The most common reported symptoms to include headache and dizziness followed by encephalopathy and delirium. Among the complications noted are Cerebrovascular accident, Guillian barre syndrome, acute transverse myelitis, and acute encephalitis. The most common peripheral manifestation was hyposmia. It is further noted that sometimes the neurological manifestations can precede the typical features like fever and cough and later on typical manifestations develop in these patients. Hence a high index of suspicion is required for timely diagnosis and isolation of cases to prevent the spread in neurology wards. We present a narrative review of the neurological manifestations and complications of COVID-19. Our aim is to update the neurologists and physicians working with suspected cases of COVID-19 about the possible neurological presentations and the probable neurological complications resulting from this novel virus infection.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets and preclinical and clinical studies suggest that TH, thyroid receptor β (TR-β) analogs, and synthetic analogs specific to liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD.

Our hypothesis that controlled ozone applications interfere into the redox balance of the biological organism (first published in 1998 with a preclinical trial on protecting the liver from CCl4 intoxication), has been verified over the last 2 decades in reactive oxygen species (ROS)-induced mitochondrial pathologies, such as rheumatoid arthritis, osteoarthritis, aging processes, diabetes-2 and in prevention of intoxications. Low-dose ozone acts as a redox bioregulator: The restoration of the disturbed redox balance is comprehensible in a number of preclinical and clinical studies by a remarkable increase of the antioxidant repair markers, here mainly shown as glutathione increase and a reduction in oxidative stress markers, mainly malondialdehyde. The mechanism of action is shown, relevant data are displayed, evaluated and comprehensively discussed: The repair side of the equilibrium increases by 21% up to 140% compared to the non-ozone treated groups and depending on the indication; the stress markers are simultaneously reduced, the redox system regains its balance.

Some of neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that contains memory loss and/or apathy. Alzheimer's disease is the most typical type of such neurodegenerative disease characterized by deficit of cognition and alteration of behavior. Despite the huge efforts against Alzheimer's disease, there has been yet no successful treatment for this disease. Interestingly, several possible risk genes to cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes and/or caveolae formation, suggesting that caveolae may be a therapeutic target to consider cognitive dysfunctions. Interestingly, modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptors signaling may offer a novel approach to prevent and alleviate the cognitive dysfunction. A paradigm that both GLP-1 and NMDA receptors at caveolae sites is promising and crucial for the treatment of cognitive dysfunctions has been presented here, which might also be able to modify the progression of Alzheimer's disease. This research direction may open the potential to move a clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases.

Objective: Subclinical left ventricular disfunction (LVD) is common in asymptomatic patients with type 2 diabetes (T2D). Many patients with diabetes have an impaired diastolic and systolic function. With preserved ejection fraction LV (EFLV), the latter is defined as reduced global longitudinal strain (GLS), detected using the speckle-tracking echocardiography. This study is aimed to define the long-term structural and functional disorders of the LV myocardium in patients with T2D without CVD. Methods: Of the 120 patients with and without T2D of both sexes aged from 45 to 75 years (57.11±7.9 years), included in the study in 2012-2013, only 57 responded to the follow-up study. The patients were divided into two groups: one with T2D (n=29), the other without it, control (n=28). All patients underwent transthoracic two-dimensional echocardiography with assessment of standard indicators of systolic and diastolic cardiac function, as well as GLS. In addition, all participants underwent laboratory diagnostics of carbohydrate metabolism disorders markers, NT-proBNP and CRP. The median follow-up duration was 7.2 [7.0-7.8] years. Results: During the follow-up, a statistically significant increase in the incidence of diastolic dysfunction (DD) in the type 2 diabetes group was found from 53% to 61% (p = 0.004); no significant dynamics were noted in the control group (p = 0.48). The presence of T2D significantly increases the risk of developing DD (p=0.04). The presence of T2D, increased fasting glucose levels, and an increased HOMA index were independent predictors of the development of DD. Impairment of LVEF was not observed in both groups. At the same time, the proportion of patients with reduced GLS (< -18%) increased in the T2D group (p = 0.036). A significant difference in the frequency of decreased GLS depending on T2D was demonstrated. The presence of obesity, an increase in the HOMA index and an increase in CRP levels are independent predictors of impaired GLS. Conclusions: T2D is an independent risk factor for the worsening of subclinical left ventricular dysfunction in asymptomatic patients with T2D without CVD over 7-year follow-up. Diastolic dysfunction is represented by delayed relaxation of the LV myocardium; with preserved LVEF, reduced 2D GLS identifies systolic dysfunction. The tight control of glycemia, lipidemia, blood pressure and body weight is associated with the absence of poor clinical outcomes.

Various symptoms have been reported to persist beyond acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is referred as long coronavirus disease 19 (long COVID-19). Over 65 million individuals suffer from long COVID-19. However, the causes of long COVID-19 have been largely unknown. Since long COVID-19 symptoms are observed throughout the body, vascular endothelial dysfunction may be a strong candidate to induce long COVID-19. The angioten-sin-converting enzyme 2 (ACE2), the entry receptor of SARS-CoV-2, is ubiquitously expressed in endothelial cells. We previously found that the risk factors for athero-sclerotic cardiovascular disease (ASCVD) and the history of ASCVD can be the risk for severe COVID-19, suggesting a contribution of pre-existing endothelial dysfunction to severe COVID-19. Here, we show a significant association of endothelial dysfunction with development of long COVID-19 and show that biomarkers for endothelial dysfunction in patients with long COVID-19 are also crucial players in development of ASCVD. We consider the influence of long COVID-19 on development of chronic kidney disease (CKD) and ASCVD. Furthermore, we suggest the therapeutic interventions for long COVID-19 by considering endothelial dysfunction as the treatment tar-gets for long COVID-19. Such interventions may prevent pandemic of CKD and ASCVD in post COVID-19 era.

Brucellosis is a multi-system infectious disease that exhibits with various manifestations and complications. Neurobrucellosis is a rare but serious presentation of brucellosis that can be discovered in every stages of the disease. Laboratory tests and physical examination and patient history are generally the basis for diagnosing the disease. It has both insidious and prolonged clinical course of the disease and long-term therapies. Also the most common pattern of exhibition is subacute or chronic. We reported a case of young female who had history of painless weakness in the right lower limb (proximal and distal) that started gradually and had progressed over the time, and after a month she felt weakness in the left lower limb with the same pattern. Lumbosacral Magnetic resonance imaging (MRI) with and without contrast was shown evidence of enhancement thickening of caudal equina ventral roots. Brucella antigen titer was positive, the result was 1/160. And other clinical tests were normal. Patient treated with Intravenous injection (IV) Rifampicin and Intravenous Cotrimoxazole. patient was discharged with good health and continuinng all two medications for 5 months. The descision was taken to report this case as a result of entire respond in patient’s illness after a enduring disease. Neurobrucellosis is a treatable disease in which it would be better to consider a high indication of suspicion. Due to if ignored, it may cause significant morbidity and mortality.

Neurotrophins, particularly brain-derived neurotrophic factor (BDNF), act as key regulators of neuronal development, survival and plasticity. In this review, we focus on the role of BDNF for corticostriatal plasticity in movement disorders, including Parkinson’s Disease (PD) and dystonia. We discuss the mechanisms how dopaminergic input modulates BDNF/TrkB signaling at corticostriatal synapses and the involvement of these mechanisms in neuronal function and synaptic plasticity. Disruption of these pathways can lead to aberrant plasticity, ultimately affecting motor function. Advancing our understanding of these mechanisms could pave the way towards innovative therapeutic strategies aiming at restoring neuroplasticity and enhancing motor function in these diseases.

Diffuse intrinsic pontine glioma (DIPG) is recognized as a pediatric brainstem cancer with a 0% survival rate. On a molecular basis, DIPG commonly results from mutations in histone H3, specifically a mutation in the H3K27M gene, that promotes tumorigenesis and results in presentation of this fatal brainstem tumor. DIPG is challenging to treat, as surgical intervention is inefficacious due to the location where the glioma resides. To date, traditional treatments such as radiation, chemotherapy, and immunotherapy have not increased survival rates and have only been successful at relieving symptoms. Future therapeutic approaches such as proton beam radiation, Chimeric Antigen Receptor T Cell (CAR-T) immunotherapy, and alternative epigenetic pharmaceuticals are under investigation for potential benefits. Various clinical trials have also explored these treatment procedures to discover potential increases in survival rates in both animal and human studies. In this review, we will evaluate the pathology and molecular characteristics of DIPG, the current and future approaches to DIPG treatment; and, lastly, we will discuss clinical trials that have been completed to develop successful treatment options.

Stenting is an alternative to endarterectomy for the treatment of carotid artery stenosis. However, stenting is associated with a higher risk of procedural stroke secondary to distal thromboembolism. Hybrid stents with a micromesh layer have been proposed to address this complication. We developed a micropatterned thin film nitinol (M-TFN) covered stent designed to prevent thromboembolism during carotid intervention. This innovation may obviate the need or work synergistically with embolic protection devices. The proposed double layered stent is low-profile, thromboresistant, and covered with a M-TFN that can be fabricated with fenestrations of varying geometries and sizes. The M-TFN was created in multiple geometries, dimensions, and porosities by sputter deposition. The efficiency of various M-TFN to capture embolic particles was evaluated in different atherosclerotic carotid stenotic conditions through in vitro tests. The covered stent prevented emboli dislodgement in the range of 70-96% during 30min duration tests. In vitro vascular cell growth study results showed that endothelial cell elongation, alignment and growth behaviour silhouettes significantly enhance specifically on the diamond-shape M-TFN with the dimensions of 145µm×20µm and a porosity of 32%. Future studies will require in-vivo testing. Our results demonstrate that M-TFN has a promising potential for carotid artery stenting.

Progress in understanding the pathogenesis and treatment of Alzheimer's disease (AD) is based on the recognition of the primary causes of the disease, which can be deduced from the knowledge of risk factors and biomarkers measurable in the early stages of the disease. Insights into risk factors and the time course of biomarker abnormalities point to a role for mitochondrial dysfunction and oxidative stress in the onset and development of AD. Coenzyme Q10 (CoQ10) is a lipid antioxidant and electron transporter in the mitochondrial electron transport system. The availability and activity of CoQ10 is crucial for proper mitochondrial function and cellular bioenergetics. Based on the mitochondrial hypothesis of AD and the hypothesis of oxidative stress, the regulation of the efficiency of the oxidative phosphorylation system by means of CoQ10 can be considered promising in restoring the mitochondrial function impaired in AD, or in preventing the onset of mitochondrial dysfunction and the development of amyloid and tau pathology in AD.

The placenta is a vital organ of pregnancy, regulating adaptation to pregnancy, gestational-parent/fetal exchange and ultimately fetal development and growth. Not surprisingly, in cases of placental dysfunction - where aspects of placental development or function become compromised - adverse pregnancy outcomes can result. One common placenta-mediated disorder of pregnancy is preeclampsia (PE), a hypertensive disorder of pregnancy with a highly heterogeneous clinical presentation. The wide array of clinical characteristics observed in pregnant individuals and neonates of a PE pregnancy are likely the result of distinct forms of placental pathology underlying the PE diagnosis, explaining why no one common intervention has proven effective in the prevention or treatment of PE. The historical paradigm of placental pathology in PE highlights an important role for utero-placental malperfusion, placental hypoxia and oxidative stress, and a critical role for placental mitochondrial dysfunction in the pathogenesis and progression of the disease. In the current review, the evidence of placental mitochondrial dysfunction in the context of PE will be summarized, highlighting how altered mitochondrial function may be a common feature across distinct PE subtypes. Further, advances in this field of study and therapeutic targeting of mitochondria as a promising intervention for PE will be discussed.

The thyroid gland secretes essential hormones for the growth regulation and the metabolic activity of the body. Thyroid dysfunction includes many conditions that can indirectly affect dental treatments. Therefore, the practitioner must be aware of these pathologies and their signs and symptoms in order to elaborate specific dental treatment plans, thus avoiding any per- and/or postoperative complications. Moreover, the dentist can help in the screening of undiagnosed thyroid dysfunction among patients.

Proteins need to be located in appropriate spatiotemporal contexts to carry out their diverse biological functions. Mislocalized proteins may lead to a broad range of diseases, such as cancer and Alzheimer’s disease. Knowing where a target protein resides within a cell will give insights into tailored drug design for a disease. As the gold validation standard, the conventional wet lab uses fluorescent microscopy imaging, immunoelectron microscopy, and fluorescent biomarker tags for protein subcellular location identification. However, the booming era of proteomics and high-throughput sequencing generates tons of newly discovered proteins, making protein subcel-lular localization by wet-lab experiments a mission impossible. To tackle this concern, in the past decades, artificial intelligence (AI) and machine learning (ML), especially deep learning methods, have made significant progress in this research area. In this article, we review the latest advances in AI-based method development in three typical types of approaches, including sequence-based, knowledge-based, and image-based methods. We also elaborately discuss existing challenges and future directions in AI-based method development in this research field.

Psychotherapy is a comprehensive biological treatment modifying complex underlying cognitive, emotional, behavioral, and regulatory responses in the brain, leading patients with mental illness to a new interpretation of the sense of self and others. Psychotherapy is an art of science integrated with psychology and/or philosophy. Neurological science studies the neurological basis of cognition, memory, and behavior as well as the impact of neurological damage and disease on the functions, and their treatment. Both psychotherapy and neurological science deal with the brain; nevertheless, they continue to stay polarized far. Existential phenomenological psychotherapy (EPP) has been in the forefront of meaning-centered counseling for almost a century. The phenomenological approach in psychotherapy originated in the works of Martin Heidegger, Ludwig Binswanger, Medard Boss and Viktor Frankl, and it has been committed to account for the existential possibilities and limitations of one’s life. EPP provides philosophically rich interpretations and empowers counseling techniques to assist mentally suffering individuals by finding meaning and purpose of life. The approach has proven to be effective in treating mood and anxiety disorders. This narrative review article demonstrates the development of EPP, the therapeutic methodology, evidence-based accounts of its curative techniques, current understanding of mood and anxiety disorders in neurological science, and a possible converging path to translate and integrate meaning-centered psychotherapy and neuroscience, concluding that the existential phenomenological psychotherapy potently plays a synergistic role with the currently prevailing medication-based approaches for the treatment of mood and anxiety disorders.

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits, often associated with the development of neurodegenerative diseases. The formation of reactive oxygen species (ROS) and oxidative stress have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice, we observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus). This elevation was accompanied by astrogliosis, microgliosis and the accumulation of amyloid precursor protein (APP). Concurrently, r-mTBI mice displayed impaired motor learning and spatial memory deficits. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as gliosis, oxidative stress, axonal damage, and white matter damage. These findings underscore the role of NHE1 upregulation in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 as a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function.

KV channel-interacting proteins (KChIPs) belong to a family of Ca2+-binding EF-hand proteins that are able to bind to the N-terminus of the KV4 channel α-subunits. As the auxiliary subunit, KChIPs are critically involved in regulating the amplitude and gating properties of KV4 channels by modulating their cell surface trafficking, voltage-dependent activation, inactivation kinetics, and recovery rate from inactivation. IKs, ICa,L, and INa can also be regulated by KChIPs. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the KV4 currents. Interestingly, all KChIPs can act as transcription factors to control the expression of genes involved in pain, memory, and circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of many diseases, such as arrhythmia, heart failure, Alzheimer's disease, etc. In this review, we summarize the research progress of KChIPs in their structural properties, physiological functions, and pathological roles in disease progression, and provide an overview of the therapeutic potential of KChIPs as pharmacological targets for associated disorders.

CLIPPERS which stand for Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, is a chronic inflammatory disorder of the central nervous system. The aetiology of CLIPPERS remains unclear, although its pathogenesis shows immune-mediated processes. The diagnosis of CLIPPERS is challenging without a specific biomarker hence, it is important to consider if both the clinical and radiological features are consistent with the diagnosis, or rather any other disease that mimics CLIPPERS. The Authors present a case of a 40-year-old Female patient diagnosed with CLIPPERS syndrome in India. Differential diagnosis, clinical and MRI characteristics of CLIPPERS syndrome, and treatment approaches are discussed.

Imaging-based biomarkers have developed as an effective tool in neurology, providing vital understandings of the structural, functional, and molecular changes associated with neurological disorders. Imaging techniques such as magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and computed tomography (CT) have been widely employed to record disease-related alterations in the brain. These techniques provide a wide range of biomarkers, such as functional connectivity patterns, volumetric measurements, molecular imaging agents, and perfusion parameters, enabling the correct identification of neurological disorders. These biomarkers have proven useful in early diagnosis, disease progression tracking, therapy response prediction, and surgical planning. This review emphasizes the various obstacles and limitations that are associated with imaging-based biomarkers. Technical constraints, standardization obstacles, ethical concerns, regulatory challenges, and cost-effectiveness concerns all offer substantial barriers to wider use. It is vital to overcome these challenges if imaging biomarkers are to be successfully integrated into routine clinical practice. Imaging technology advancements like high-resolution imaging, multimodal imaging, and artificial intelligence-based analysis hold immense promise for imaging-based biomarkers in the future. While more study and standardization are needed, their ongoing development and integration into clinical practice have the potential to revolutionize the diagnosis, treatment, and management of neurological disorders, resulting in better patient care and outcomes.

This study investigated the effects of fish oil (FO) treatment, particularly enriched with eicosapentaenoic acid (EPA), on obesity induced by a high-fat diet (HFD) in mice. The investigation focused on elucidating the impact of FO on epigenetic modifications in white adipose tissue (WAT) and the involvement of adipose-derived stem cells (ASCs). C57BL/6j mice were submitted to a control diet or a HFD for 16 weeks, treated (or not) with FO for the last 8 weeks. WAT was removed for RNA and protein extraction, while ASCs were isolated, cultured, and treated with Leptin. All samples were analyzed using functional genomics tools, including PCR-array, RT-PCR and Western Blot assays. Mice receiving HFD displayed increased body mass, fat accumulation, and altered gene expression associated with WAT inflammation and dysfunction. FO supplementation attenuated these effects, a potential protective role against HFD-induced obesity. Analysis of H3K27 revealed HFD-induced changes in histone, which were partially reversed by FO treatment. The study further explored leptin signaling in ASCs, suggesting a potential mechanism for ASC dysfunction in the leptin-rich environment of obese WAT. Overall, FO supplementation demonstrated efficacy in mitigating HFD-induced obesity, influencing epigenetic and molecular pathways, and shedding light on the role of ASCs and leptin signaling in WAT dysfunction associated with obesity.

Background: The incidence of metabolic dysfunction-associated steatohepatitis (MASH)-related hepatocellular carcinoma (HCC) is increasing annually with a rise in the incidence of obesity and metabolic syndrome. Based on preliminary reports regarding the potential association of HCC and periodontitis, this study aimed to analyze the involvement of periodontal bacteria as well as the oral and intestinal bacterial flora in MASH-related HCC (MASH-HCC). Methods: Forty-one patients with MASH and 19 with MASH-HCC who completed survey questionnaires, underwent periodontal examinations, and subjected to sample collection (saliva, mouth-rinsed water, feces, and peripheral blood) participated in the study. Bayesian network analysis was used to analyze the causation between various factors, including MASH-HCC, examinations, and bacteria. Results: The occupancy rate of the genus Fusobacterium in the intestinal bacterial flora was significantly higher in in the MASH-HCC group than in the MASH group (p = 0.002), whereas that of Butyricicoccus (p = 0.022) and Roseburia (p &lt; 0.05) was significantly lower. Bayesian network analysis revealed the absence of periodontal pathogenic bacteria and enteric bacteria affecting HCC. However, HCC directly affected the periodontal bacterial species Porphyromonas gingivalis, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in the saliva, as well as the genera Lactobacillus, Roseburia, Fusobacterium, Prevotella, Clostridium, Ruminococcus, Trabulsiella, and SMB53 in the intestine. Furthermore, P. gingivalis in the oral cavity directly affected the genera Lactobacillus and Streptococcus in the intestine. Conclusion: MASH-HCC directly affects periodontal pathogenic and intestinal bacteria, and P. gingivalis may affect the intestinal bacteria associated with gastrointestinal cancer.

Delve into the dynamic realms of neuroscience, neurology, and psychiatry with this groundbreaking editorial, unveiling the intricate mechanisms of brain function and dysfunction. Explore the latest advancements in molecular biology, genetics, epigenetics, pharmacology, and neuroimaging that are revolutionizing our understanding of neurological and psychiatric disorders. Uncover the challenges and gaps in translating cutting-edge research into practical clinical applications, aiming to enhance the lives of patients and their families. Discover the pivotal role of neuroplasticity in reshaping the brain's adaptability throughout life, alongside the promising potential of non-invasive brain stimulation techniques like transcranial magnetic stimulation and transcranial direct current stimulation. Embark on a journey of innovation and collaboration as researchers and clinicians strive to bridge the gap between bench and bedside, offering hope for improved diagnosis, prevention, and treatment of complex neurological and psychiatric conditions. Join us in this exploration of transformative ideas and novel interventions that hold the key to a brighter future for individuals and society.

1. Background and Objective: Spontaneous Intracranial Hemorrhage (ICH) is a catastrophic medical condition associated with significant morbidity and mortality. As the accumulation of unbound iron following ICH contributes to secondary brain injury, deferoxamine, an approved chelation drug, has become the center of attention. At the same time, its therapeutic remains a matter of dispute. This double-blinded Randomized Controlled Trial (RCT) aims to investigate the therapeutic potential of deferoxamine in neurological and radiological aspects. 2. Methods and Materials: The study enrolled 42 participants diagnosed with spontaneous ICH and confirmed by CT scan, randomly assigning them to either the deferoxamine treatment group or the placebo control group. While the control group received the routine treatment plus a placebo, the treatment group received routine treatment conjugated with 7.5 mg/kg of deferoxamine per hour intravenously over the first three days. The study compared hematoma and edema volume, GCS score, and mortality rates between the two groups. Our study employed rigorous randomization and blinding procedures to ensure unbiased results. 3. Results: There was a significant (p<0.05) improvement in patients' GCS up until the fourth day, but no significant difference was noted afterward. In addition, the volume of both edema and hematoma was significantly lower in the intervention group, as well as the length of stay, intubation requirement, and mortality. 4. Discussion: Deferoxamine administration can, at least in a short timeframe, improve neurological and radiological parameters.

Background and Objectives: Intramedullary spinal cord tumors (IMSCT) are rare entities. Especially, a location in the upper cervical spine as a highly eloquent region carries the risk of postoperative neurological deficits, such as tetraparesis or respiratory dysfunction. Evidence for respiratory dysfunction is scarce. The aim of this study was to describe the early and late postoperative clinical course of this highly eloquent tumours. Patients and Methods: This is a single-centre retrospective cohort study. We included 35 patients with IMSCT at levels of craniocervical junction to C4 who underwent surgical treatment between January 2008 and December 2022. The authors analysed the patients' preoperative status, tumour- and surgery-specific characteristics, and follow-up functional status. Results: The study cohort included 22 patients with grade II ependymoma (62.9%), 2 low-grade astrocytomas (5.7%), 2 glioblastomas (5.7%), 6 hemangioblastomas (17.1%), 2 metastases (5.7%), and 1 patient with partially intramedullary schwannoma (2.9%). Gross total resection was achieved in 76% of patients. Early dorsal column related symptoms and motor deterioration occurred in 64% and 44% of patients, respectively. At a follow-up of 3.27 ± 3.83 years, 43% and 33% of patients preserved postoperative sensory and motor deterioration, respectively. The median McCormick Scale grade was 2 in the preoperative and late postoperative periods, respectively (p=0.0897, α=0.05). Only two out of 35 patients (5.7%) developed new intermittent respiratory dysfunction, of whom two were transient. There were no surgery-related deaths. Conclusions: The surgery of IMSCT of the upper cervical spine could be performed without major procedure-related risk. Roughly a half of the patients develop new neurological deficit in the immediate postoperative period. However, most of the patients still maintain functional independence. The rate of respiratory insufficiency is low and is strongly influenced by the rapid neurological deterioration in high-grade tumours.

The coexistence of SAH with T2DM is a common comorbidity. In this present study, we investigated the link between altered plasma antioxidant trace elements (ATE: Manganese, Selenium, Zinc and Copper) and fatty acids ratio (FAR: polyunsaturated/saturated) imbalance as transition biomarkers between vascular pathology (SAH) to metabolic pathology (T2DM). Our data revealed strong correlation between plasma ATE and FAR profile which is modified during SAH-T2DM association compared to healthy group. This relationship is mediated by lipotoxicity (simultaneously prominent visceral adipose tissue lipolysis, significant flow of non-esterified free fatty acids release, TG-Chol-dyslipidemia, high association of Total SFA, Palmitic acid, Arachidonic acid and PUFA 6/ PUFA 3; drop in tandem of PUFA / SFA and EPA+DHA); oxidative stress (lipid peroxidation confirmed by TAS depletion and MDA raise, concurrently drop of Zn/Cu-SOD, GPx, GSH, Se, Zn, Se/Mn, Zn/Cu; concomitantly enhance Cu, Mn and Fe); endothelial dysfunction (endotheline-1 increase); athero-thrombogenesis risk (concomitantly raise of ApoB100/ApoA1, Ox-LDL, tHcy and Lp(a)) and inflammation (higher of Hs-CRP, Fibrinogen and Ferritin). Our study open to new therapeutic targets and to better dietary management, such as to establish dietary ATE and PUFA 6 / PUFA 3 or PUFA / SFA reference values for atherosclerotic risk prevention in hypertensive-diabetics patients.

Functional neurological disorders (FND) are relatively frequent disabling conditions. Given their complexity, multidisciplinary rehabilitation is envisaged. Whole-body cryostimulation (WBC) represents a promising adjuvant treatment, mainly because of its anti-inflammatory and exercise-mimicking effects. Here, we propose a novel use of WBC in a wheelchair-ridden 61-year-old woman diagnosed with FND and other comorbidities, who, after several therapeutic and rehabilitation failures, underwent a multidisciplinary rehabilitation program including WBC. The 4-week program included physiotherapy, nutritional intervention, psychological support, and WBC. Questionnaires to assess disease impact, pain level, perceived fatigue and sleep quality were administered. At discharge, improvements in body composition, haematological biomarkers, physical performance, and questionnaire scores were observed. The patient was able to walk with a walker for medium distances, even outdoors. We observed unprecedented improvements, particularly in functional parameters and questionnaire scores. Although we cannot ascertain to which extent WBC per se contributed to the improvements measured, subjective reporting and our clinical observation were that WBC, the only intervention not previously experienced by the patient, acted as a booster for the rehabilitation interventions. Further research will be necessary to rule out any possible placebo effect and to assess the effects of WBC on FND.

The gut-brain axis (GBA) represents a complex, bidirectional communication network that intri-cately connects the gastrointestinal tract with the central nervous system (CNS). Understanding and intervening in this axis opens a pathway for therapeutic advancements. In light of this, the current review assesses the effectiveness of neuromodulation techniques in treating neurological and gastrointestinal disorders by modulating the GBA, involving key elements such as gut micro-biota, neurotrophic factors, and proinflammatory cytokines. Through a comprehensive literature review encompassing PubMed, Google Scholar, Web of Science, and the Cochrane Library, and analyzing 182 relevant articles, this research highlights how neuromodulation can positively impact the management of functional gastrointestinal disorders (FGIDs), chronic pain, inflammation, and a range of GI disorders like Crohn's disease and ulcerative colitis. Despite existing challenges, the ability of neuromodulation to adjust disrupted neural pathways, alleviate pain, and mitigate in-flammation is significant in improving the quality of life for patients, thereby offering exciting prospects for future advancements in patient care.

Increased soluble endoglin (sENG) were observed in human brain arteriovenous malformations (bAVMs), and overexpression of sENG with vascular endothelial growth factor (VEGF)-A induced dysplastic vessel formation in mouse brain. However, the underlying mechanism of sENG-induced vascular malformations is not clear. While evidence suggests the role of sENG as a pro-inflammatory modulator, increased microglial accumulation and inflammations were observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that sENG with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, there were increased microglial activation around dysplastic vessels with expression of NLRP3, inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs while it decreased IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to release angiogenic/inflammatory responses which may be involved in EC dysfunction. Our study suggests the contribution of microglia in the pathology of sENG-associated vascular malformations.

Modified mRNAs (modRNAs) are an emerging delivery method for gene therapy. In particular, the modRNA-based COVID-19 vaccines have proven that modRNA is a safe and effective therapeutic tool. Moreover, modRNA has the potential to treat various human diseases including cardiac dysfunction. Acute myocardial infarction (MI) is a major cardiac disorder that currently lacks curative treatment options. MI is commonly accompanied by fibrosis and impaired cardiac function. Our group previously demonstrated that the matricellular protein CCN5 inhibits cardiac fibrosis (CF) and improves cardiac dysfunction. However, it remains elusive whether the early intervention of CF under stress conditions is beneficial or more detrimental due to potential adverse effects such as left ventricular (LV) rupture. To obtain acute CCN5 expression, we used modRNA-mediated gene transfer in a mouse MI model. To evaluate CCN5 activity, we established two independent experimental schemes: 1) preventive intervention and 2) therapeutic intervention. Cardiac function and structural changes were measured by echocardiography and magnetic resonance imaging. Finally, fibrosis and the underlying molecular pathway were analyzed by western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. The modRNA-CCN5 gene transfer successfully ameliorated CF and enhanced cardiac function in both preventive and therapeutic interventions without LV rupture or any adverse cardiac remodeling. Conclusively, early intervention in CF by modRNA-CCN5 gene transfer is an efficient and safe therapeutic modality for treating MI-induced heart failure without adverse structural remodeling.

Portal myofibroblasts (PMF) are known to be critical in bile duct injury, but their role in liver fibrogenesis remains underexplored. Thy-1, an adhesion molecule integral to fibroblasts, relevant in fibrogenesis and detectable in serum as soluble Thy-1 (sThy-1), is expressed by PMF but not hepatic stellate cells in vitro. This study aimed to elucidate the correlation between Thy-1 expression in liver histology and sThy-1 levels in serum with the degree of liver fibrosis in patients with primary biliary cholangitis (PBC) and metabolic dysfunction associated steatotic liver disease (MASLD). Liver histology samples were stained for Thy-1 and sThy-1 was measured using an enzyme-linked immunosorbent assay (ELISA). In patients with PBC and MASLD, portal Thy-1 expression significantly correlated with increased fibrosis. The sinusoidal Thy-1 expression also significantly correlated with increased fibrosis in patients with PBC (p

Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including CYP1A2, CYP2C9, CYP4F2, GSTP1, and NAT2 that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolizers compared to patients in Group A, did not show an improvement in 5mC levels during follow-up. Furthermore, there were significant differences in phenotype distribution between patient Groups A and B for several SNPs associated with transporter genes (ABCB1, ABCC2, SLC2A9, SLC39A8, and SLCO1B1) and pathogenic genes (APOE, NBEA, and PTGS2). These findings appear to suggest that the interplay between pharmacogenomics and DNA methylation has important implications for improving treatment outcomes in patients with brain-related disorders.

Muscle mass at admission is important to survive stroke, and stroke-induced sarcopenia is a serious problem because of its poor prognosis. Muscle mass measurement and monitoring are essential for appropriate re-habilitation and nutrition management. Several methods are used to assess skeletal muscle mass in stroke, such as computed tomography (CT), ultrasonography, bioelectrical impedance analysis, dual-energy X-ray absorptiometry, biomarkers, and anthropometrics. In stroke, a head CT is used to estimate muscle mass by measuring the temporal muscle. However, it is mostly retrospectively conducted due to radiation exposure. After stroke, limb muscle atrophy and diaphragm dysfunction are observed using ultrasound. However, ultrasound requires an understanding of the methods and skill. A bioelectrical impedance analysis can be used to assess muscle mass in patients after a stroke unless they have dynamic fluid changes. Dual-energy X-ray absorptiometry is used for follow-up after hospital discharge. Urinary titin N-fragment and serum C-terminal agrin fragment reflect muscle atrophy after stroke. Anthropometrics may be useful with limited resources. We summarized the features of each measurement and proved the recent evidence to properly measure and monitor skeletal muscle mass after stroke.

Background: The incidence of spinal metastatic disease has risen with improved cancer survivorship. Separation surgery, the current standard surgical treatment, does not fully address spinal deformity. Advances in operative management warrant reevaluating maximal tumor resection and anterior column reconstruction with corpectomy. Methods: An IRB-approved retrospective single-center review of 63 patients was performed. Demographics, tumor characteristics, clinical and radiographic data, treatments, and neurological and survival outcomes were analyzed. Results: The mean age at presentation was 63.5 ± 9.6 years (range, 37-84 years) and 28 patients (44.4%) were female. Functional outcomes, measured by KPS, RAND-36 survey scores and Oswestry Disability Index all improved postoperatively (pre- vs postop: 70 to 80 (p=0.0056), 26.5 to 46.4 (p=0.0081), and 28.9 to 16.9 (p=0.0613), respectively). Spinal alignment also improved, with Cobb angle measurements showing a reduction in spinal kyphosis from -5 to 0 (p=0.021). Nine patients (14.5%) had non-fatal postoperative complications. The median OS for this cohort was 14.4 months (range, 0.6-145.0 months) with median follow-up time of 15.5 months. Conclusion: In oligometastatic spinal disease patients with good functional status, corpectomy for decompression of neural elements, deformity correction, and spinal stabilization is associated with improvements in pain and functional outcomes without overwhelming morbidity.

We have previously shown that the transmembrane protein ODZ1 promotes cytoskeletal remodelling of glioblastoma (GBM) cells and invasion of the surrounding parenchyma through activation of a RhoA-ROCK pathway. We also described that GBM cells can control the expression of ODZ1 through transcriptional mechanisms triggered by binding of IL-6 to its receptor and a hypoxic environment. Epidermal growth factor (EGF) plays a key role in the invasive capacity of GBM. However, the molecular mechanisms that enable tumor cells to acquire the morphological changes to migrate out from the tumor core have not been fully characterized. Here we show that EGF is able to induce the expression of ODZ1 in primary GBM cells. We analysed the levels of EGF receptor (EGFR) in 20 GBM primary cell lines and found expression in 19 of them by flow cytometry. We selected two cell lines that do or do not express EGFR and found that EGFR-expressing cells responded to EGF ligand by increasing ODZ1 at the mRNA and protein level. Moreover, blockade of EGF-EGFR binding by Cetuximab, inhibition of the p38 MAPK pathway or siRNA-mediated knockdown of MAPK11 (p38 MAPK) reduced the induction of ODZ1 in response to EGF. Overall, we show that EGF may activate an EGFR-mediated signalling pathway through p38 MAPK, to upregulate the invasion factor ODZ1, which may initiate morphological changes for tumor cells to invade the surrounding parenchyma. These data identify a new candidate of the EGF-EGFR pathway for novel therapeutic approaches.

Plants and plant-derived food products have been used for medicinal purposes since the ancient. Medicinal Plant-based functional foods or plant-based dietary compounds are a re-emerged interest for their therapeutic benefits and nutritive supports which has implicated in healthcare systems across the world. Neurological disorders are one of the greatest threats to public health and according to the World Health Organization, about 100 million people are affected globally by several neurological and mental ailments. In a traditional medication system, medicinal plants have been applied as both neuro-therapeutic purposes and micro-macro nutrients provider for the wellbeing of psychological states e.g. anti-depressant, anti-anxiety, anti-convulsions, anti-dementia, anti-psychotic, etc. Herein, it is a topic of great interest to present a conceptual aspect by reviewing relevant scientific literature about the plant-based functional foods or bioactive phytochemicals for the prevention and treatment of mental and neurological disorders. From the literature assessment, we have found that nutritional neuroscience is becoming an advanced research discipline and there has been a growing pile of evidence concerning the therapeutic use of plant-based functional foods and/or plant-derived food compounds for the management of neurologic health, evolving with promising impact over the time.

It is widely known that vitamin D receptors have been found in neurons and glial cells and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. The vitamin D helps the regulation of neurotrophin, neural differentiation and maturation, through the control operation of growing factors synthesis (ie NGF and GDNF), the trafficking of the septo-hyppocampal pathway, and the control of the synthesis process of different neuromodulators (such as Ach, DA, and GABA). Based on these assumptions, we have written this review in order to summarize the potential role of vitamin D in neurological pathologies. The work could be titanic, and might result very fuzzy and even incoherent, if we would not have conjectured to taper our first intentions and devoted our interests towards three mainstreams: demyelinating pathologies, vascular syndromes and neurodegeneration. Due to the lack of effective therapeutic options, a part from the disease modifying strategies, the role of different risk factors should be investigated in neurology, as far as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.

Magnetic resonance (MR) image acquisitions are usually time-consuming, limiting utilization in neuroimaging. For multiple sclerosis (MS) patients, MR imaging plays a major role in drug therapy decision-making. The purpose of this study was to evaluate whether an ultrafast, T2-weighted (T2w), deep-learning-enhanced (DL), echo-planar-imaging-based (EPI) fluid-attenuated inversion recovery (FLAIR) sequence (FLAIRUF) that has been targeting neurological emergencies so far might even be an option to detect MS lesions of the brain compared to conventional FLAIR sequences. Therefore, 17 MS patients were enrolled prospectively in this exploratory study. Standard MR protocols and ultrafast acquisitions were conducted at 3 tesla (T), including three-dimensional (3D)-FLAIR, turbo/fast spin echo (TSE)-FLAIR, and FLAIRUF. Inflammatory lesions were grouped by size and location. Lesion conspicuity and image quality were rated on an ordinal five-point Likert scale, and lesion detection rates were calculated. Statistical analyses were performed to compare results. Altogether, 568 different lesions were found. Data indicated no significant differences in lesion detection (sensitivity and positive predictive value [PPV]) between FLAIRUF and axially reconstructed 3D-FLAIR (lesion size ≥ 3 mm × ≥ 2 mm) and no differences in sensitivity between FLAIRUF and TSE-FLAIR (lesion size ≥ 3 mm total). Lesion conspicuity in FLAIRUF was similar in all brain regions except for superior conspicuity in the occipital lobe and inferior conspicuity in central brain regions. Further findings include location-dependent limitations of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) as well as artifacts such as spatial distortions in FLAIRUF. In conclusion, FLAIRUF could potentially be an expedient alternative to conventional methods for brain imaging in MS patients since the acquisition can be performed in a fraction of time while maintaining good image quality.

Metabolic dysfunction associated fatty liver disease (MAFLD), a globally prevalent chronic liver disease, has only limited pharmacological options. Both metformin and Ganwei, a botanical supplement containing a potent inducer for glycine N-methyltransferase (GNMT), have shown great promise for MAFLD. We conducted a 4-arm, randomized, placebo-controlled trial to investigate the safety and efficacy of metformin and Ganwei for MAFLD. Between September 2021 and March 2023, 64 patients with MAFLD were received metformin alone, Ganwei alone, combination of metformin and Ganwei, and placebo for 6 months. The primary MAFLD outcome was assessed by control attenuation parameter (CAP) and kilopascal (kPa) scores for liver steatosis and fibrosis, utilizing FibroScan. At 6 months after treatment, significant MAFLD improvements were observed in patients treated with Ganwei alone (repeated measures ANOVA test, p = 0.048 for both CAP and kPa scores). By employing a 6-point steatosis grade scale, the Ganwei alone arm exhibited a statistically better improvement than the placebo-controlled arm (mean score 1.1±1.9 vs. 0.1±0.7, p &lt; 0.01). In addition, patients in the Ganwei alone arm showed significant quality-of-life improvements. There was no serious adverse events observed. Our study demonstrated that Ganwei can be an effective treatment option for MAFLD patients. Clinical trial registration: NCT06244550.

Background/Objectives: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Cardiovascular disease (CVD) is the leading cause of mortality in MASLD patients, therefore, the therapeutic interventions for MASLD should improve coronary risk factors such as obesity, diabetes and dyslipidemia, in addition to improving liver function. The evidence on effect of sodium-glucose cotransporter 2 inhibitors (SGLT2is) which have beneficial pharmacological properties for MASLD, especially the long-term effects, on the progression of MASLD in Asian population is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at the National Center for Global Health and Medicine, Kohnodai Hospital, Japan. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between April 1, 2014 and March 31, 2018. We collected the data on metabolic parameters, including blood tests and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. The 3-year-SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein-cholesterol, triglyceride and non-high-density lipoprotein-cholesterol (HDL-C) and significantly increased HDL-C. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, the long-term SGLT2is treatment may be an ideal therapy for MASLD patients.

Pain is a multifaceted multisystem disorder that adversely affects neuro-psychological processes. This study compares the effectiveness of central-stimulation (tDCS) and peripheral-stimulation (TENS) in pain-inhibition during a cognitive-task in healthy volunteers and to observe potential neuro-cognitive improvements. Healthy eighty volunteers went through a complete experimental protocol comprising pain-induction (CPT), administration of tDCS/TENS, EEG-data acquisition, and cognitive assessments. The protocol for this study is categorized into 04-groups: G1(Control), G2(TENS), G3(Anodal-tDCS), and G4(Cathodal-tDCS). Paired t-tests (p

Recent advancements in cognitive neuroscience, particularly in Electroencephalogram (EEG) signal processing, image generation, and brain-computer interfaces (BCI), have opened up new avenues for research. This study introduces a novel framework, Bridging Artificial Intelligence and Neurological Signals (BRAINS), which leverages the power of AI to extract meaningful information from EEG signals and generate images. The BRAINS framework addresses the limitations of traditional EEG analysis techniques, which struggle with nonstationary signals, spectral estimation, and noise sensitivity. Instead, BRAINS employs Long Short-Term Memory (LSTM) networks and contrastive learning, which effectively handle time-series EEG data and recognize intrinsic connections and patterns. The study utilizes the MNIST dataset of handwritten digits as stimuli in EEG experiments, allowing for diverse yet controlled stimuli. The data collected is then processed through an LSTM-based network employing contrastive learning and extracting complex features from EEG data. These features are fed into an image generator model, producing images as close to the original stimuli as possible. This study demonstrates the potential of integrating AI and EEG technology, offering promising implications for the future of brain-computer interfaces.

Revealing the underlying pathomechanisms of neurological and psychiatric disorders, searching for new biomarkers, and developing novel therapeutics all require translational research. In vivo and in vitro disease models have been instrumental in casting light on complex polygenic, multifactorial, and heterogeneous disease mechanisms. In the most recent years, advanced preclinical models have revealed the intriguing interaction of sex/gender and aging with the pathogenesis and clinical manifestations of psychiatric and neurological diseases. However, despite these advancements, there is still a great deal of work to be done to fully comprehend the underlying mechanisms of these diseases and to develop treatments that can significantly improve the lives of those who suffer from them. The current challenge in the field of neurological and psychiatric diseases is to develop disease-modifying, effective treatments for these complex and long-lasting debilitating conditions with a high burden of disease.The first edition of the research topic ‘Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models’ reinforces translational research playing a critical role in bridging the gap between basic research and clinical applications. Also, it provides a platform for researchers to share their findings and advancements in translational research in this field. This new collection gathers 25 papers offering insights into the latest advancements in translational research and potential new avenues for treatments. These papers cover various topics, including the development of new preclinical models, the use of in vitro and in vivo methods, and the application of qualitative and quantitative research methods.

A large body of evidence, replicated in many mouse models of Alzheimer Disease (AD), demonstrated the therapeutic efficacy of oral rapamycin. Administration of m-TOR inhibitors (mTOR-Is), early after the clinical onset, greatly diminished cognitive impairment, amyloid angiopathy, intracellular beta Amyloid and neurofibrillary tangles load. The daily intake of rapamycin has always been 2.24g/Kg/24h. In humans the maximal tolerated oral dose is a few milligrams/day, and at this dosage patients are severely immunosuppressed. Thanks to rapalogs’ scarce CNS-related side effects, we administered intracerebroventricularly (ICV) high doses of the mTOR-I everolimus in a mouse model of AD (3xTg-AD) without significant systemic effects. The instability of the liquid formulation at body temperature (BT) made the treatment very short. Nevertheless, the efficacy of the treatment was high and much longer lasting than expected. In order to set up a thermostable, translational liquid formulation of mTOR-Is, we loaded everolimus in distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) micelles by the thin layer method. The formulation we obtained maintained over 95% of activity after 14 days at BT. We can envision short, potentially periodic ICV treatments in AD patients which replicate results obtained on animal models. The treatment could benefit also Tuberous Sclerosis and Multiple Sclerosis patients.

Pericytes are increasingly recognized as being important in the control of blood-brain barrier permeability and vascular flow. Research on this important cell type has been hindered by widespread confusion regarding the phenotypic identity and nomenclature of pericytes and other perivascular cell types. In addition, pericyte heterogeneity and mouse-human species differences have contributed to confusion. Herein we summarize our present knowledge on the identification of pericytes and pericyte subsets in humans, primarily focusing on recent findings in humans and nonhuman primates. Precise identification and definition of pericytes and pericyte subsets in humans may help us to better understand pericyte biology and develop new therapeutic approaches specifically targeting disease-associated pericyte subsets.

Cardiovascular disease (CVD), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disa-bility. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to even greater health and economic burden as the global average life expectancy increases and consequently the world’s population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.

Cardiovascular diseases (CVD) account for about 17.3 million annual deaths worldwide. 85% of these deaths occurred as a result of myocardial infarction (MI) and stroke. Chronic heart diseases, such as arterial hypertension (AH), coronary heart disease, various cerebrovascular diseases, dilated and hypertrophic cardiomyopathies are widespread, with a fairly high incidence of mortality and disability. Most of these diseases are characterized by cardiac arrhythmias, conduction and contractility disorders. Additionally, interruption of the electrical activity of the heart, the appearance of extensive ectopic foci and heart failure are all symptoms of a number of severe hereditary diseases. The molecular mechanisms leading to the development of CVD are associated with impaired permeability and excitability of cell membranes and mainly caused by dysfunction of cardiac Ca2+ channels. Acquired channelopathies are caused by metabolic disorders, increased tone of the sympathetic nervous system, age-related changes that lead to deterioration of coronary blood flow and hemodynamics. Currently known channelopathies, such as the long or short QT syndromes, Brugada and Lenegre syndromes, catecholaminergic polymorphic ventricular tachycardia, etc., are congenital and genetic disorders caused by mutations of genes "responsible" for the conductive properties of certain channel-forming proteins, including pore-forming subunits of Ca2+ channels. Over the past 50 years, more than 100 varieties of ion channels have been found in the cardiovascular system cells. The relationship between the activity of these channels and cardiac pathology, as well as the general cellular biological function, has been intensively studied on several cell types and experimental animal models in vivo и in situ. In this review, we discuss the origin of Ca2+ channelopathies and the role of Ca2+ channels of various types: L- R-, T-types voltage-gated calcium channels, RyR2, non-selective hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, transient receptor potential (TRPC, TRPM7, TRPA1) channels in the development of cardio-vascular pathology.

Over the last decades, cellular immunotherapy has revealed its curative potential. However, the inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes, in addition to the various strategies put in place to circumvent these effects. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer are discussed. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features is key to the development of improved cellular immunotherapies.

The recently emerged coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) is the newest threat to human health. It has already infected more than half a million people worldwide, leading to a lot of deaths. Although it causes mild flu-like disease in most patients, lethality may increase to more than 20% in elderly subjects, especially those with comorbidities, like hypertension, diabetes or lung and cardiac disease, and the mechanisms are still elusive. Common symptoms at the onset of illness are fever, cough, myalgia or fatigue, headache, and diarrhea or constipation. Interestingly, respiratory viruses have also placed themselves as relevant agents for CNS pathologies. Here we discuss several CNS related features, referred by several patients, especially at the beginning of the disease. Thus, we also discuss the possibility by which SARS-CoV-2 may affect the olfactive system of patients, either directly or indirectly.

Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSD

One of the hallmarks of the SARS-CoV-2 infection has been the inflammatory process that played a role in its pathogenesis, resulting in mortality within susceptible individuals. This uncontrolled inflammatory process leads to severe systemic symptoms via multiple pathways, however, the role of endothelial dysfunction and thrombosis have not been truly explored. This review aims to highlight the pathogenic mechanisms of these inflammatory triggers leading to thrombogenic complications. There are direct and indirect pathogenic pathways of the infection that are examined in detail. We also describe the case of carotid artery thrombosis in a patient following the SARS-CoV-2 infection, while reviewing the literature on the role of ACE2, the endothelium, and the different mechanisms by which SARS-CoV-2 may manifest both acutely and chronically. We also highlight differences from the other coronaviruses that have made this infection pandemic with similarities to the influenza virus.

Despite extensive research, the links between the accumulation of glycosaminoglycans (GAGs) and the clinical features seen in patients suffering from various forms of Mucopolysaccharidoses (MPSs) have yet to be further elucidated. This is particularly true for the neuropathology of these disorders, even though the neurological symptoms are currently incurable, even in the cases where a dis-ease-specific therapeutic approach does exist. One of the best ways to get insights on the molecular mechanisms driving that pathogenesis is the analysis of patient-derived cells. Yet, not every pa-tient-derived cell holds potential to recapitulate relevant disease features. For the neurodegenerative forms of these diseases in particular, it is challenging to grow neuronal cultures that accurately represent them because of the obvious inability to access live neurons. This scenario changed sig-nificantly since Yamanaka et al. published their protocol for induction of pluripotent stem cells (SC) from adult human fibroblasts. From then on, a series of differentiation protocols to generate neurons from induced pluripotent stem cells (iPSC) was developed and extensively used for disease mod-eling. Currently, human iPSC and iPSC-derived cell models have been generated for several MPS and numerous lessons were learnt from their analysis. Here we review most of those studies, not only listing the currently available MPS iPSC lines and their derived models, but also summarizing how they were generated and the major information different groups have gathered from their analysis. Finally, and taking into account that iPSC generation is a laborious/expensive protocol that holds significant limitations, we also comment on a tempting alternative to establish MPS pa-tient-derived neuronal cells in a much more expedite way by taking advantage of the existence of a population of multipotent SC in human dental pulp, to establish mixed neuronal and glial cultures.

Cardiac arrest may cause significant hypoxic-ischemic injury leading to coma, seizures, myoclonic jerks, or status epilepticus. Mortality is high but accurate prognostication is challenging. A multimodal approach is employed, in which electroencephalograph (EEG) forms a key part with several recognised patterns of prognostic significance. In this retrospective study, clinical and qualitative features of the EEG of patients admitted to the Intensive Care Unit (ICU) at Kingston General Hospital following cardiac arrest from 2017-2020 were reviewed. The study included 81 adult patients (>18 years). Outcome was assessed using the Cerebral Performance Category as 1-2 (favourable) or 3-5 (unfavourable). EEG patterns were divided into groups within the highly malignant, malignant, and benign patterns described in the literature. There were a wide range of causes and 22% had a favourable outcome. Highly malignant, malignant, and benign patterns were associated with survival in 0%, 78% and 100% respectively and favourable outcomes in 0%, 44% and 100%. All patients with seizures died and 94% with myoclonus had unfavourable outcomes. In contrast, EEG reactivity and improvement on follow-up EEG was associated with a favourable outcome. In conclusion, highly malignant EEG, seizures and myoclonus were associated with unfavourable outcome, while patient with malignant EEG had better outcome.

The split of the brain into two hemispheres is pivotal to human existence, enabling incompatible versions of the world, with quite different priorities and values, to exist concomitantly. Neuroimaging techniques are usually the adopted methods to assess hemispherical bias. However, can differences in thinking orientation, behavioural style, and personality emerging from laterality be observed without the use of neuroimaging techniques? This paper investigates whether a personality test based on the Five-factor model (FFM) is also able to identify hemispherical bias. It does so by testing five hypotheses on personality differences related to handedness. The aim is to contribute to the instantiation of the FFM in neuroscience by testing its validity against the neuroscientific literature on brain laterality. The findings pointed to no statistically significant differences due to handedness in three out of five personality traits (namely, Neuroticism, Conscientiousness and Extraversion). As to the other two traits – Openness and Agreeableness – the hypotheses were only partially confirmed by the data, as the relevant difference found was not between left-handed and right-handed groups, but between ambidextrous and the others.

T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically ‘exhausted’ in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.

The fundamental goal of modern medicine is to increase human life expectancy. Currently, most of the patients in hospitals with different clinical profiles are elderly and senile subjects, with a high incidence of comorbidities, as well as concomitant age-related changes in peripheral tissues. One such change is sarcopenia, a progressive loss of muscle mass, strength, and muscle function that is associated with a high risk of adverse outcomes, leading to an increased risk of disability and death among older adults. The mechanisms of development of sarcopenia are currently being actively studied. This narrative review presents the issues of epidemiology, pathophysiology, and diagnostic criteria for sarcopenia. The relationships between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD) with possible promising directions for the treatment of this comorbid pathology are considered.

Erectile dysfunction (ED) is the inability to achieve or maintain an erection during sexual performance. ED is one of the most common and neglected complications of diabetes. Almost 35-75% of diabetic men around the world suffer from ED. Although the exact mechanism by which diabetes causes ED is not well understood. However, several studies suggested it may be related to damage to the nerve and vessels that supply the penis.

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from the infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn, increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules each of which can downregulate ACE2, while the infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19 associated neurological disorders.

Ophelia syndrome is characterized by the coincidence of severe neuropsychiatric symptoms, classical Hodgkin lymphoma, and the presence of antibodies to the metabotropic glutamate 5 receptor (mGluR5). Little is known about the pathogenetic link between these symptoms and the role that anti-mGluR5-antibodies play. We investigated lymphoma tissue from patients with Ophelia syndrome and with isolated classical Hodgkin lymphoma by quantitative immunocytochemistry for mGluR5-expression. Further, we studied the L-1236, L-428, L-540, SUP-HD1, KM-H2, and HDLM-2 classical Hodgkin lymphoma cell lines by FACS and Western blot for mGluR5-expression, and by transcriptome analysis. mGluR5 surface expression differed significantly in terms of receptor density, distribution pattern, and percentage of positive cells. Highest expression levels were found in the L-1236 line. RNA-sequencing revealed more than 800 genes that were higher expressed in the L-1236 line in comparison to the other classical Hodgkin lymphoma cell lines. High mGluR5-expression was associated with upregulation of PI3K/AKT and MAPK pathways and of downstream targets (e.g. EGR1) known to be involved in classical Hodgkin lymphoma progression. Finally, mGluR5 expression was increased in the classical Hodgkin lymphoma-tissue of our Ophelia syndrome patient in contrast to five classical Hodgkin lymphoma-patients without autoimmune encephalitis. Given the association of encephalitis and classical Hodgkin lymphoma in Ophelia syndrome, it is possible that mGluR5-expression on classical Hodgkin lymphoma cells not only drives tumor progression but also triggers anti-mGluR5 encephalitis even before classical Hodgkin lymphoma becomes manifest.

Iron deficiency in the fetal and neonatal period (perinatal iron deficiency) bodes poorly to neuro-development. Given its common occurrence and the negative impact on brain development, a screening and treatment strategy that is focused on optimizing brain development in perinatal iron deficiency is necessary. Pediatric societies currently recommend a universal iron supple-mentation strategy for full-term and preterm infants that does not consider individual variation in the body iron status and could lead to under-treatment or over-treatment. Moreover, the focus is on hematological normalcy and not optimal brain development. Several serum iron indices and hematological parameters in the perinatal period are associated with risk of abnormal neurodevelopment, suggesting their potential use as biomarkers for screening and monitoring treatment in infants at risk for perinatal iron deficiency. A biomarker-based screening and treatment strategy that is focused on optimizing brain development will likely improve outcome in perinatal iron deficiency.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Although characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset and complications. While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. Furthermore, large scale genome sequencing studies revealed that many genes previously reported as causative of HCM in fact have little or no evidence of disease association. These findings thus call for a re-evaluation of the sarcomere-centered view of HCM pathogenesis. Here, we summarize our current understanding of sarcomere-independent mechanisms of cardiomyocyte hypertrophy, highlight the role of extracellular signals in cardiac fibrosis, and propose an alternative but integrated model of HCM pathogenesis.

As in glaucoma and other optic neuropathies cellular dysfunction often precedes cell death, sensitive assessment of retinal ganglion cell (RGC) function represents a key outcome measure for neuroprotective strategies aimed at targeting distressed but still viable cells. Here we offer a conceptual framework to identify progressive stages of RGC dysfunction leading to cell death in mouse models of glaucoma and other optic neuropathies based on non-invasive pattern electroretinogram (PERG), to differentiate phenotypic and altered RGC response dynamics, to assess susceptibility to stressors and to assess reversible dysfunction.

Mild traumatic brain injury (mTBI) or concussion accounts for the bulk of all head injuries and represents a major health concern. Although an mTBI event may not manifest in neurobehavioral impairment, repeated injuries, known as repeated mTBI (rmTBI), can result in a cumulative effect that may progress to long-term cognitive and functional deficits. To date, there is no FDA-approved drug for TBI in general and rmTBI in particular. In previous studies, we have demonstrated the neuroprotective role of mitoquinone (MitoQ), a mitochondrial antioxidant, in an open head injury model and a model of repeated mild TBI (rmTBI) at a chronic time point (30 days). In this work, we set out to assess the neuroprotective potential of MitoQ at acute (3 days) and subacute time points (7 days) post-injury in a controlled cortical impact model of rmTBI. C57BL/6 male mice were injected intraperitoneally with MitoQ (5 mg/kg) one hour after the first mTBI, and three days after the first injury in both the 3-day and 7-day MitoQ + rmTBI subgroups, with an additional injection four days after the second injection in the 7-day group. Cognitive function was evaluated using the Morris water maze (MWM) while gross and fine motor functions were evaluated by the pole climbing, grip strength, and ladder rung tests. Dihydroethidium (DHE) staining was performed to evaluate oxidative stress while qRT-PCR was used to measure the gene expression of different antioxidant enzymes. Also, immunofluorescence staining was performed on brain tissue to assess the degree of microgliosis and astrocytosis. Our results showed that MitoQ conferred significant protection on days 3 and 7 post-injury against fine motor function impairment induced by rmTBI. Moreover, MitoQ enhanced cognitive function and reduced astrogliosis, microgliosis, and levels of oxidative stress on day 7 post-injury. However, antioxidant gene expression generally remained unaffected. In light of our results, MitoQ administration may be considered a preventive approach that helps to alleviate the neurological manifestations associated with rmTBI early before symptoms progress to long-term deficits.

Human Parechoviruses, officially known as Parechovirus A (PeV-A), is associated with mild gastrointestinal and respiratory illness in young children, however, they may also give rise to Central Nervous System (CNS) infections and neonatal sepsis. While studies have delved into the detection of PeV-A in different populations, the detection of PeV-A in Hispanic populations in Latin American countries is not well-known. The aim of this study was to determine the presence of PeV-A in respiratory, gastrointestinal, and neurological clinical samples of pediatric patients in Panama. Two hundred samples of pediatric patients with a negative diagnosis for the main respiratory viruses, rotavirus and neurological viruses such as herpesvirus, enterovirus and cytomegalovirus, collected between 2014 and 2015, were analyzed by real-time RT-PCR. Eight positive PeV-A infections were detected, 2 in respiratory samples, 5 in stool samples and one detected in cerebrospinal fluid. This is the fisrt report of PeV-A in Panamá.

Oil-Gan, also known as emblica, is the fruit of the genus Phyllanthus emblica L. The fruits of these trees are high in nutrients and have excellent effects on health care and development values. There are many methods for the management of diabetic nephropathy (DN). However, there is a lack of effective drugs for treating DN from throughout the disease course. The primary aim of this study was to examine the protective effects (including urine analyses, the measurement of inflammatory cytokine levels, and histological examination) and mechanisms of action of an ethyl acetate extract of P. emblica (EPE) on db/db mice, an animal model of diabetic nephropathy, as well as a secondary aim of examining the expression levels of protein kinase Cα (PKCα) in the kidney and its downregulation of vascular endothelial growth factor (VEGF) and fibrosis gene transforming growth factor-β1 (TGF-β1) by Western blot analyses. Eight db/m C57BLKS/J mice were used as the control group. Forty db/db mice were randomly divided into five groups. Treatments included vehicle, EPE1, EPE2, EPE3 (at doses of 100, 200, or 400 mg/kg EPE), or the comparative drug aminoguanidine for 8 weeks. After 8 weeks of treatment, blood samples were collected for analyses of blood glucose, insulin, and HbA1c levels, and pancreatic and kidney tissues were dissected for histological analyses. The present study indicated that the administration of EPE to db/db mice effectively controlled hyperglycemia and hyperinsulinemia by markedly lowering blood glucose, insulin, and glycosylated HbA1c levels. Administration of EPE to db/db mice decreased the levels of BUN and creatinine both in blood and urine and reduced urinary albumin excretion and the albumin creatine ratio (UACR) in urine. Moreover, EPE treatment decreased the blood levels of inflammatory cytokines, including kidney injury molecule-1 (KIM-1), C-reactive protein (CRP), and NLR family pyrin domain containing (NLRP3). Our findings showed that EPE not only had antihyperglycemic effects but also improved renal function in db/db mice. Histological examination of the kidney by immunohistochemistry indicated that EPE can improve kidney function by ameliorating glomerular morphological damage following glomerular injury; alleviating proteinuria by upregulating the expression of nephrin, a biomarker of early glomerular damage; and inhibiting glomerular expansion and tubular fibrosis. Moreover, the administration of EPE to db/db mice increased the expression levels of p- PKCα/t-PKCα but decreased the expression levels of VEGF and renal fibrosis biomarkers (TGF-β1, collagen IV, p-Smad2, p-Smad3, and Smad4), as shown by Western blot analyses. These results implied that EPE as a supplement has a protective effect against renal dysfunction through the amelioration of insulin resistance as well as the suppression of nephritis and fibrosis in a DN model.

Metabolic dysfunction associated fatty liver disease (MAFLD) has gained worldwide attention as a public health problem. Nonetheless, lack of enough mechanistic knowledge restrains effective treatments. It is known that T3 regulate hepatic lipid metabolism, and mitochondrial function. Liver dysfunction of T3 contributes to MAFLD, but its role is not fully understood. Objective: To evaluate the role of T3 dysfunction in the progression of MAFLD in an animal model. Method-ology: Male/adult Sprague Dawley rats (n=20) were allocated to a control group (standard di-et–2.93kcal/g) and diet group (CDHF–4.3kcal/g). Euthanasia took place in the 28th week. D3 ac-tivity and expression, UCP2 and D1 expression, REDOX status, mitochondrial, Krebs cycle and endoplasmic reticulum homeostasis in liver tissue were measured. Results: We observed an in-crease in D3 activity/expression (P<0.001) related to increased TBARS and carbonyls and GSH reduction in the MAFLD group (P<0.05). There was a T3-dependent decrease in UCP2 expression (P=0.01), mitochondrial capacity, respiratory activity with increased endoplasmic reticulum stress in the MAFLD group (P < 0.001). Surprisingly, in and environment with lower T3 levels we observed an augmented alpha-ketoglutarate dehydrogenase (KGDH) and glutamate dehydro-genase (GDH) enzymes activity (P<0.05). Conclusion: Induced D3, triggered by changes in the REDOX state, decreases T3 availability, and hepatic mitochondrial capacity. The Krebs cycle en-zymes were altered as well as reticulum stress. Taken together, these results shed new light on the role of T3 metabolism in MAFLD and new treatment opportunities.

Introduction: The disease caused by Coronavirus-2019 (COVID-19) was initially described in December 2019. Severe acute respiratory syndrome type 2 (Sars-Cov-2) is responsible for an important multisystem inflammatory spectrum. Cardiovascular conditions have been reported with an estimated frequency of 8-28%. In this context, transthoracic echocardiography associated with the analysis of the two-dimensional Global Longitudinal Strain (GLS) of the left ventricle derived from Speckle Tracking emerges as a promising modality. Objective: This study aims to evaluate the applicability of GLS and segmental deformity assessment in detecting subclinical myocardial dysfunction in patients that recovered from COVID-19 infection. Methods: The observational study involved 18 patients (mean age 52 years) with recent evidence of COVID-19 infection that underwent detailed echocardiographic evaluation with GLS, and cardiac magnetic resonance (CMR) according to segmental assessment results. The degree of correlation between the methods was analyzed and a systematic literature review was also conducted. Results: The mean left ventricular ejection fraction (LVEF) was 57.50 ± 9.98%. Only 16.6% of patients had reduced LVEF. The average GLS was – 18.70 ± 3.54% and in 44% of cases only one myocardial segment was affected, particularly the inferolateral basal. CMR revealed inflammatory cardiomyopathy. Discussion: Subclinical myocardial involvement is associated with major adverse cardiac events. Literature review supports the use of GLS for detecting early cardiac involvement. Conclusion: Speckle-tracking echocardiography has been shown to have clinical utility in a variety of settings and to offer superior prognostic value with a potential to enhance subclinical detection of myocardial changes in patients after COVID-19 infection.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and memory loss. Oxidative stress (OS) has emerged as a central element in the pathophysiology of AD, linking various pathological features including amyloid-β (Aβ) plaque formation, tau hyperphosphorylation, and synaptic dysfunction. This review comprehensively examines the role of OS in AD, focusing on the mechanisms of reactive oxygen species (ROS) production, mitochondrial dysfunction, and their impact on neuronal integrity. Additionally, the review highlights recent advances in antioxidant therapy. Elevated ROS levels in the aging brain exacerbate oxidative damage to lipids, proteins, and DNA, contributing to neuronal atrophy and synaptic loss. Mitochondrial dysfunction further amplifies OS, disrupting cellular energy metabolism and promoting neurodegeneration. Despite the strong association between OS and AD, antioxidant therapies have shown inconsistent clinical outcomes. Emerging strategies targeting offer promising avenues for therapeutic intervention. This review highlights the need for a multifaceted approach in understanding and mitigating OS-related damage in AD, aiming to pave the way for more effective treatments and improved patient outcomes.

Coronary microvascular dysfunction (CMD) is a clinical entity linked with various risk factors that significantly affect cardiac morbidity and mortality. Hypertension, one of the most important, causes both functional and structural alterations in the microvasculature, promoting the occurrence and progression of microvascular angina. Endothelial dysfunction and capillary rarefaction play the most significant role in the development of CMD among patients with hypertension. CMD is also related to several hypertension-related morphological and functional changes in the myocardium in the subclinical and early clinical stages, including left ventricular hypertrophy, interstitial myocardial fibrosis, and diastolic dysfunction. This indicates the fact that CMD, especially if associated with hypertension, is a subclinical marker of end-organ damage and heart failure, particularly the one with preserved ejection fraction. This is why it is important to search for microvascular angina in every patient with hypertension and chest pain not associated with obstructive coronary artery disease. Several highly sensitive and specific non-invasive and invasive diagnostic modalities have been developed to evaluate the presence and severity of CMD, but also to investigate additional complications that can affect further prognosis, especially among those with hypertensive heart disease. Although various pharmacological and interventional treatments demonstrated certain clinical effects, integrated diagnostic and therapeutic algorithms are necessary to reduce the burden of this emerging condition.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one third of global population and became the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) also remain significant challenges to liver health even in the 21st century. The coexistence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. Thorough understanding of the pathobiological interlink and interactions between MAFLD and these two chronic viral hepatitis infections are crucial for appropriate management of patients. We update these interlinks in this comprehensive clinical review.

Oligodendrocytes are myelinating cells of the central nervous system, which are generated by progenitor oligodendrocytes as a result of maturation processes. The main function of mature oligodendrocytes is to produce myelin, a lipid-rich multi-lamellar membrane that wraps tightly around neuronal axons, isolating them and facilitating nerve conduction through saltatory propagation. The myelination process requires the consumption of a lot of energy and a high metabolic turnover. Mitochondria are essential organelles which regulate many cellular functions including the energy production through oxidative phosphorylation. Any mitochondrial dysfunction impacts cellular metabolism and negatively affects the health of the organism. If the functioning of the mitochondria is unbalanced the myelination process is impaired. At the end of myelination, oligodendrocytes synthesize about 40% of the total lipids present in the brain. Since lipid synthesis occurs in the cellular endoplasmic reticulum, the alteration of this organelle can lead to partial or deficient myelination, triggering numerous neurodegenerative diseases. In this review the main dysfunctions of oligodendrocytes caused by exogenous or endogenous stimuli will be investigated. Furthermore, the oligodendrocyte reactions to excessive mitochondrial oxidative stress and an altered regulation of the functioning of the endoplasmic reticulum will be discussed.

Candida spondylodiscitis (CS) is a rare disease, for which therapeutic option are limited to fluconazole or echinocandins and the treatment should be administered up to 12 months. In case of reduced azole susceptibility, there is a scarcity of therapeutic options with adequate bone penetration and limited toxicity. We report the first case of successful use of rezafungin for a spondylodiscitis due to Candida parapsilosis with reduced susceptibility to azoles. The patient, affected by paraplegia and short bowel syndrome, was diagnosed with CS with culture on vertebral biopsy guided by a 18-FDG-PET/CT scan. He received rezafungin 200 mg weekly for 26 weeks, after 10 weeks of previous antifungal treatment. He had a full clinical, radiologic and biochemical response to the therapy with rezafungin, with no adverse effects. Rezafungin is a promising therapy for Candida osteomyelitis, especially when first line therapies are ineffective or contraindicated.

Objective. To evaluate serum neuronal and inflammatory biomarkers in asphyctic newborns treated with hypothermia alone or hypothermia plus melatonin, and whether biomarkers correlate with neurodevelopmental outcomes. Design. This is a pilot multicentre, randomised, controlled, double blind clinical trial. Neuronal glial fibrillary acidic protein (GFAP), granulocyte-macrophage colony-stimulating factor (GM-CSF), and inflammatory cytokines (interleukin (IL)-1, IL-2, IL-7 and IL-13) were measured in serum samples at hospital admission (T0), 24 hours (T1), 72 hours (T2) and 7-10 days of age (T3). Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales, Gross Motor Function Classification System (GMFCS) and the Tardieu scale) were performed at 6 and 18 months. Setting: Level 3 neonatal intensive care unit. Patients and interventions: 25 newborns were recruited. The treated patients received a daily dose of intravenous melatonin, 5 mg per kg body weight, for 3 days. Results. After adjusting the data for severity, in the group treated with melatonin, there is a decrease in plasma levels of GM-CSF, IL-2 and IL-13 at T1 compared to placebo, as well as, at T2, in GM-CSF concentrations, as well as IL-7 and IL-13 at T3. Evolutionarily, we found a significant decrease in GM-CSF concentrations in the treatment group compared to placebo, with no differences for the rest of the biomarkers. It is noteworthy that the sustained decrease in GM-CSF and inflammatory cytokines IL-2, IL-7 and IL-13 correlated with better neurodevelopmental outcomes at 6 and 18 months. Conclusions. In neonates with hypoxic-ischemic encephalopathy, the addition of iv melatonin to hypothermia therapy affects the plasma concentration of biomarkers in the first week of life, with a high correlation with long-term neurological prognosis.

Abstract Cerebral microbleed(s) (CMBs) are increasingly being viewed not only as a marker for cerebral small vessel disease (SVD) but also as having an increased risk for the development of stroke (hemorrhagic/ischemic) and aging-related dementia. Recently, brain endothelial cell activation and dysfunction and blood-brain barrier dysfunction and/or disruption have been shown to be associated with SVD, enlarged perivascular spaces, and the development and evolution of CMBs. CMBs are a known disorder of cerebral microvessels that are visualized as 3-5mm, smooth, round or oval, and hypointense (black) lesions seen only on T2*-weighted gradient recall echo or susceptibility-weighted sequences on MRI images. CMBs (a global problem) are known to occur with high prevalence in community-dwelling older individuals. Since our current global population is the oldest recorded in history and only expected to continue to grow, we can only expect the health care burdens associated with CMBs to also grow. CMBs should raise a red flag regarding the increased risk of large symptomatic neurologic intracerebral hemorrhages. Importantly, CMBs are also currently regarded as markers of diffuse vascular and neurodegenerative brain damage. Thus, it is essential that we try to learn as much as we can about their development, evolution, and their relation to impaired cognition, dementia, and neurodegeneration.

Recent research has unveiled intriguing insights suggesting that the body's immune system may be implicated in Parkinson's disease (PD) development. Studies have observed disparities in pro-inflammatory and anti-inflammatory markers between PD patients and healthy individuals. This finding underscores the potential influence of immune system dysfunction in the genesis of this condition. A dysfunctional immune system can serve as a primary catalyst for systemic in-flammation in the body, which may contribute to the emergence of various brain disorders. The identification of several genes associated with PD, as well as their connection to neuroinflamma-tion, raises the likelihood of disease susceptibility. Moreover, advancing age and mitochondrial dysfunction can weaken the immune system, potentially implicating them in the onset of the dis-ease, particularly among older individuals. Compromised integrity of the blood-brain barrier could facilitate the immune system's access to brain tissue. This exposure may lead to encounters with native antigens or infections, potentially triggering an autoimmune response. Furthermore, there is mounting evidence supporting the notion that gut dysbiosis might represent an initial trigger for brain inflammation, ultimately promoting neurodegeneration. In this comprehensive review, we will delve into the numerous hypotheses surrounding the role of both innate and adaptive immunity in PD.

Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries [1]. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease [1], all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under transcriptional regulation of both the nuclear and the mitochondrial genome, to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, to dynamics which regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function to cause disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs including the ovary (oocyte and granulosa cell), uterus, placenta, and circulation to cause reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in transgenerational transmission of PCOS and metabolic disorders.

Zinc is a highly abundant cation in the brain, where it is essential for cellular function, including transcription, enzymatic activity, and cell signaling. However, zinc can also trigger injurious cascades in neurons, contributing to the pathology of neurodegenerative diseases. Mitochondria, critical for meeting the high energy demands of the central nervous system (CNS), are a principal target of the deleterious actions of zinc. An increasing body of work suggests that intracellular zinc, can, under certain circumstances, contribute to neuronal damage by inhibiting mitochondrial energy processes, including dissipation of the mitochondrial membrane potential, leading to ATP depletion. Additional consequences of zinc-mediated mitochondrial damage include reactive oxygen species (ROS) generation, mitochondrial permeability transition, and calcium deregulation. Zinc can also induce mitochondrial fission, resulting in mitochondrial fragmentation, as well as inhibition of mitochondrial motility. Here, we review the known mechanisms responsible for the deleterious actions of zinc on the organelle, within the context of neuronal injury associated with neurodegenerative processes. Elucidating the critical contributions of zinc-induced mitochondrial defects to neurotoxicity and neurodegeneration may provide insight into novel therapeutic targets in the clinical setting.

Breast cancer is a serious disease and the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are urgently needed. Repurposing FDA-approved drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on breast cancer cell lines including patient derived cell lines. Proguanil caused apoptosis through increased production of ROS and consequent decrease of mitochondrial membrane potential, mitochondrial respiration, and ATP production rates. ROS generation by proguanil was up to 3-fold higher when compared to the control. Proguanil treatment increased the expression of Bax, p-H2AX, cleaved-caspase 9, cleaved PARP, and down-regulated bcl-2 and survivin in breast cancer cell lines. The enlargement of 4T1 breast tumors in female Balb/c mice was suppressed by 55% through daily oral administration of 20mg/kg of proguanil. Western blot analyses of proguanil- treated tumors showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Proguanil proved to be an efficient in vitro and in-vivo inhibitor of breast cancer cells, hence should be considered further for clinical investigation against breast cancer.

Post-viral fatigue syndrome (PVFS) encompasses a wide range of complex neuroimmune disorders of unknown cause characterized by disabling post-exertional fatigue, myalgia and joint pain, cognitive impairments, unrefreshing sleep, autonomic dysfunction, and neuropsychiatric symptoms. It includes myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and more recently post-COVID-19 condition (Long COVID). To date, there are no definitive clinical case criteria and no FDA-approved pharmacological therapies for PVFS. Given the current lack of effective treatments, there is a need to develop novel therapeutic strategies for these disorders. Mitochondria, the cellular organelles responsible for tissue energy production, have recently garnered attention in research into PVFS due to their crucial role in cellular bioenergetic metabolism in these conditions. Accumulating literature has identified a link between mitochondrial dysfunction and low-grade systemic inflammation in ME/CFS, FM, and Long COVID. To address this issue, this article aimed to critically review the evidence relating to mitochondrial dysfunction in the pathogenesis of these disorders; in particular, to evaluate the effectiveness of coenzyme Q10 supplementation on chronic fatigue and pain symptoms as a novel therapeutic strategy for the treatment of PVFS.

Cardiac hypertrophy is an adaptive response to various pathological insults including hypertension. However, sustained hypertrophy can cause impaired calcium regulation, cardiac dysfunction, and remodeling, accompanied by cardiac fibrosis. Our previous study identified miR-25 as a regulator of SERCA2a, and that inhibition of miR-25 improved cardiac function and reduced fibrosis by restoring SERCA2a expression in a murine heart failure model. However, the precise mechanism underlying the reduction of fibrosis by miR-25 inhibition remains unclear. Therefore, we postulate that miR-25 may have additional targets that contribute to regulating cardiac fibrosis. Using in silico analysis, Krüppel-like factor 4 (KLF4) was identified as an additional target of miR-25. Further experiments confirmed that KLF4 was directly targeted by miR-25 and that its expression was reduced by long-term treatment with Angiotensin II, a major hypertrophic inducer. Subsequently, treatment with a miR-25 inhibitor alleviated the cardiac dysfunction, fibrosis, and inflammation induced by Angiotensin II. These findings indicate that inhibiting miR-25 not only enhances calcium cycling and cardiac function via SERCA2a restoration but also reduces fibrosis by restoring KLF4 expression. Therefore, targeting miR-25 may be a promising therapeutic strategy for treating hypertensive heart diseases.

Aim: Evaluation of role of supplementation of omega-3 polyunsaturated fatty acids on endothelial function in patients with metabolic syndrome. Methods: Total of 80 patients with metabolic syndrome were enrolled to two groups. We evaluated endothelial function in subjects before and after three-month treatment with omega-3 polyunsaturated fatty acids in dose 2.4g daily (800mg 3 times a day) vs placebo. Using the Endo-PAT2000 device (Itamar Medical Ltd. Caesarea, Israel), reactive hyperemia index – a parameter of endothelial function and augmentation index– a parameter of arterial stiffness were measured. Plasmatic level of glutation peroxidase, homocysteine, apolipoprotein B and lipoprotein (a) were also evaluated. Results: The average values of reactive hyperemia index before the treatment with n-3PUFA was 1.62 ± 0.42 , whereas 1.96 ± 0.62 at the end of the study (p<0.005). Augmentation index changed from 14.66 ± 19.55 to 9.21 ± 15.64 after the treatment (p=0.003). We also observed statistically significant decrease of apolipopotein B (0.94 ± 0.36 vs 1.13 ± 0.35, p = 0.001) and homocysteine (19.31 ± 5.29 vs. 13.78 ± 3.05, p = 0.001) and increase of the glutathion perxidase plasma levels (41.65 ± 8.90 vs. 45.20 ± 8.01), p=0.001. Conclusion: We have observed significant improvement of the endothelial function in subjects with metabolic syndrome treated with omega-3 polyunsaturated fatty acids in dose 2.4g daily.

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA-containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction of inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.

The Coronavirus Disease 2019 (COVID-19) pandemic has resulted in a significant surge of critically ill patients and an unprecedented demand on intensive care services. The rapidly evolving understanding of pathogenesis, limited disease specific evidence and demand-resource imbalances have posed significant challenges for intensive care clinicians. COVID-19 is a complex multisystem inflammatory vasculopathy with a significant mortality implication for those admitted to intensive care. Institutional strategic preparation and meticulous intensive care support are essential to maximising outcomes during the pandemic. The significant mortality variation observed between institutions and internationally, despite a single aetiology and uniform presentation, highlights the potential influence of management strategies on outcome. Given that optimal organ support and adjunctive therapies for COVID-19 have not yet been well defined by trial-based outcomes, strategies are predicated on existing literature and experiential learning. This review outlines the relevant pathophysiology and management strategies for critically ill patients with COVID-19, and shares some of the collective learning accumulated in a high volume Severe Respiratory Failure centre in London.

Background/Objectives: Vitamin B12 deficiency can cause variable symptoms, which may be irreversible if not diagnosed and treated in a timely manner. We aimed to develop a widely accepted expert consensus to guide the practice of diagnosing and treating B12 deficiency. Methods: We conducted a scoping review of the literature published in PubMed since January 2003. Data were used to design a two-round Delphi survey to study the level of consensus among 42 experts. Results: The panelists agreed on the need for educational and organizational changes in the current medical practices for diagnosing and treating B12 deficiency. Recognition of clinical symptoms should receive the highest priority in establishing the diagnosis. There is agreement that the serum B12 concentration is useful as a screening marker, whereas methylmalonic acid or homocysteine can support the diagnosis. Patient lifestyle, disease history and medications can provide clues to the cause of B12 deficiency. Regardless of the cause of the deficiency, initial treatment with parenteral B12 was regarded as the first choice for patients with acute and severe manifestations of B12 deficiency. The use of high-dose oral B12 at different frequencies may be considered for long-term treatment. Prophylactic B12 supplementation should be considered for specific high-risk groups. Conclusions: There is a consensus that clinical symptoms need to receive more attention in establishing a diagnosis. B12 laboratory markers can support the diagnosis. The severity of clinical symptoms, the causes of B12 deficiency and the treatment goals govern decisions regarding the route and dose of B12 therapy.